Proprietary: This proposal includes trade secrets and other proprietary or confidential information of Highland Instruments and is being provided for use by the National Institutes of Health (NIH) for the sole purpose of evaluating this SBIR proposal. No other rights are conferred. This proposal and the trade secrets and other proprietary or confidential information contained herein shall further not be disclosed in whole or in parts, outside of NIH without Highland Instrument's permission. This restriction does not limit the NIH's right to use information contained in the data if it is obtained from another source without restriction. This legend applies to the entire proposal, including, but not limited to the Abstract, Introduction, Specific Aims, Research Plan (all components), Commercialization Plan, and Human Subject's Sections of this proposal. Abstract In patients with Parkinson?s Disease (PD), postural instability is a leading cause of disability, dependence on others, and mortality. Current treatments for PD, including pharmacological and surgical methods, have limited impact on postural instability. Physical therapy (PT) for PD is becoming increasingly used as a means to induce exercise-dependent plasticity that can result in significant benefits for patient balance. However, PT is still untailored to each patient need, and has not been optimized to work synergistically with other therapies in PD. In recent years, there has been an increased interest in the use of noninvasive brain stimulation (NIBS) devices for the treatment of PD and in their ability to couple their effects with PT regimens. But, ultimately conventional NIBS methods have showed minimal and inconsistent effects on PD symptoms, and in particular patient balance. It has been postulated that these techniques? limitations in focality, penetration, and targeting control translate into their limited therapeutic effects. Electrosonic Stimulation (ESStim?) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue. This proposal is focused on evaluating the therapeutic impact of ESStim in PD patients as adjunct therapy to PT. First in Phase I, we will follow 18 PD patients (9 SHAM ESStim, 9 active ESStim) undergoing PT after giving a fixed dose of ESStim for 10 days of stimulation, 20 mins/day, over a two- week period. We will assess a battery of electrophysiology, cognitive, and neurological safety markers; balance; Quality of Life (QOL) tests; the Unified Parkinson?s Disease Rating Scale (UPDRS); and sensor- based, biomechanical metrics during bradykinesia, posture, and walking abilities/gait tests over the 2-week period and for at least six weeks following the last treatment session. Next in Phase II, we will follow 40 PD patients (20 SHAM, 20 active ESStim stimulation) after providing treatment over a month (i.e., increasing treatment by 2 weeks), and assess the patients as above, but now for at least 8 weeks after treatment ends. Finally, we will test whether the effects of ESStim enhanced PT training for postural instability in PD can be guided by the baseline disease state and the effective dose of stimulation. To test this we will build and evaluate multivariate linear and generalized linear regression models to predict the clinical outcomes. We will also build MRI derived models of the stimulation fields in the brain (electrical and sonic field models) of each of the PD subjects and correlate the stimulatory field characteristics with therapeutic outcomes. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to test the effectiveness of ESStim as adjunct therapy to PT in PD patients. The results of the proposed work will serve as the basis for a future large-scale multicenter study to further validate the technique and optimize the methodology of ESStim coupled with PT for use in PD therapy.